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配体活性构象搜寻方法及其应用研究——Ⅰ.搜寻方法及凝血酶抑制剂活性构象的搜寻 总被引:4,自引:0,他引:4
在综合系统构象搜寻和配体-生物大分子对接(Dock)方法的基础上,发展了根据受体活性部位三维结构搜寻配体活性构象的搜寻方法BCSPL.用此方法搜寻了凝血酶抑制剂PPACK的活性构象,结果与晶体结构非常吻合,又用此方法搜寻了膦酰肽类和二肽、三肽类凝血酶抑制剂与人体α凝血酶结合时的活性构象,并在此基础上用分子力学计算了抑制剂与凝血酶的结合能,结果表明结合能与活性有很好的相关性,计算结果能合理地解释抑制剂与凝血酶的相互作用方式及结构与活性的关系. 相似文献
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建立短肽抑制剂与酶识别的模式──基于表面静电互补和溶剂化能的Docking计算方法 总被引:2,自引:2,他引:0
提出了把简化的接触表面静电互补模型与溶剂化能模型相结合的新的Docking计算方法.编写了计算模拟程序ESCOLD,并用于酶-短肽体系的Docking计算.对3个已知X射线晶体结构的酶-抑制剂肽链复合物中的六肽用ESCOLD重新进行了Docking计算.用溶剂化能作为评价函数,正确地预测出接近实验结果的六肽取向. 相似文献
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半乳糖凝集素是一类能够特异性识别β-半乳糖苷结构的可溶性蛋白,广泛分布于正常组织和病变组织中,在细胞黏附、细胞凋亡、炎症反应和肿瘤转移等过程具有重要作用,是治疗肿瘤、炎症及神经性疾病等多种疾病的潜在靶点.根据衍生位点的差异,按照半乳糖单取代、双取代和多取代衍生物的顺序对近十多年来基于D-半乳糖衍生的小分子半乳糖凝集素抑制剂进行分类,总结了这些抑制剂的化学合成方法及活性研究进展,期望能为高活性和高选择性的半乳糖凝集素抑制剂的设计提供思路,为靶向半乳糖凝集素的新型药物开发提供参考. 相似文献
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非肽类凝血酶抑制剂的比较分子力场分析 总被引:6,自引:0,他引:6
在血栓症和止血疗法中凝血酶起重要的生物调节作用,凝血酶抑制剂由于基溶 血栓作用成为药物设计的热点,对非肽类芳基磺酸酯系列凝血酶抑制剂进行了三维 定量构效关系研究。用Autodock方法和比较分子力场分析相结合构建了该类分子的 定量构效关系模型,得到三维等值线图。模型的传统相关系数r~2=0.956,交叉验 证系数q~2=0.681, F_(4,16) = 85.985,标准偏差S = 0.158。该模型为凝血酶抑 制剂的进一步结构改造提供了有益的启示。 相似文献
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在1BXB结构基础上, 通过分子对接方法构建木糖异构酶与抑制剂木糖醇的复合物模型, 为合理设计解除木糖醇对木糖异构酶的抑制及进一步揭示木糖醇对该酶抑制机理提供参考. 相似文献
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植物血凝素简称PHA是从菜豆中提取的一种凝集素,能激活T淋巴细胞使其增殖,含有红血球凝集素(H-PHA)和白血球凝集素(L-PHA),某些凝集素分子中含有金属离子,如Mn~(2+)、Ca~(2+)等,这些凝集素与糖结合的活力和生物活性均依赖于金属离子的存在,这表明金属离子对凝集素的活性有影响.PHA与金属离子的作用研究还未见报道,本 相似文献
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Dr. Michael Reynolds Dr. Marco Marradi Dr. Anne Imberty Dr. Soledad Penadés Dr. Serge Pérez 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(14):4264-4273
Multivalent protein‐carbohydrate interactions are involved in the initial stages of many fundamental biological and pathological processes through lectin–carbohydrate binding. The design of high affinity ligands is therefore necessary to study, inhibit and control the processes governed through carbohydrate recognition by their lectin receptors. Carbohydrate‐functionalised gold nanoclusters (glyconanoparticles, GNPs) show promising potential as multivalent tools for studies in fundamental glycobiology research as well as biomedical applications. Here we present the synthesis and characterisation of galactose functionalised GNPs and their effectiveness as binding partners for PA‐IL lectin from Pseudomonas aeruginosa. Interactions were evaluated by hemagglutination inhibition (HIA), surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays. Results show that the gold nanoparticle platform displays a significant cluster glycoside effect for presenting carbohydrate ligands with almost a 3000‐fold increase in binding compared with a monovalent reference probe in free solution. The most effective GNP exhibited a dissociation constant (Kd) of 50 nM per monosaccharide, the most effective ligand of PA‐IL measured to date; another demonstration of the potential of glyco‐nanotechnology towards multivalent tools and potent anti‐adhesives for the prevention of pathogen invasion. The influence of ligand presentation density on their recognition by protein receptors is also demonstrated. 相似文献
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Reynolds M Marradi M Imberty A Penadés S Pérez S 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(14):4264-4273
Multivalent protein-carbohydrate interactions are involved in the initial stages of many fundamental biological and pathological processes through lectin-carbohydrate binding. The design of high affinity ligands is therefore necessary to study, inhibit and control the processes governed through carbohydrate recognition by their lectin receptors. Carbohydrate-functionalised gold nanoclusters (glyconanoparticles, GNPs) show promising potential as multivalent tools for studies in fundamental glycobiology research as well as biomedical applications. Here we present the synthesis and characterisation of galactose functionalised GNPs and their effectiveness as binding partners for PA-IL lectin from Pseudomonas aeruginosa. Interactions were evaluated by hemagglutination inhibition (HIA), surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays. Results show that the gold nanoparticle platform displays a significant cluster glycoside effect for presenting carbohydrate ligands with almost a 3000-fold increase in binding compared with a monovalent reference probe in free solution. The most effective GNP exhibited a dissociation constant (K(d)) of 50 nM per monosaccharide, the most effective ligand of PA-IL measured to date; another demonstration of the potential of glyco-nanotechnology towards multivalent tools and potent anti-adhesives for the prevention of pathogen invasion. The influence of ligand presentation density on their recognition by protein receptors is also demonstrated. 相似文献
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J H Matthews T D Dinh P Tivitmahaisoon J W Ziller D L Van Vranken 《Chemistry & biology》2001,8(11):1071-1079
BACKGROUND: Two types of biaryl crosslinks can be formed with natural protein sidechains: ditryptophan and dityrosine. Biaryl crosslinks have the same topology as disulfide crosslinks, yet little is known about their effect on local peptide structure. RESULTS: Three ditryptophan-linked peptide dimers based on the sequence Ac-Leu-Trp-Ala-COX were prepared. The tripeptide dimer with -CONH(2) termini was too insoluble to study, but the tripeptide dimer with -COOMe termini crystallized from methanol/chloroform as an antiparallel beta-sheet. The tripeptide dimer with a -CONMe(2) termini adopted a slipped antiparallel beta structure in methanol/chloroform. CONCLUSIONS: These results suggest that intermolecular ditryptophan crosslinks that join the middle of peptide chains can confer a preference for antiparallel beta-sheet structure. The effect is most dramatic when both the inside and outside edges of the dimer can form hydrogen bonds as in the crystal structure of dimer 3b. 相似文献
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Cecioni S Faure S Darbost U Bonnamour I Parrot-Lopez H Roy O Taillefumier C Wimmerová M Praly JP Imberty A Vidal S 《Chemistry (Weinheim an der Bergstrasse, Germany)》2011,17(7):2146-2159
The design of multivalent glycoconjugates has been developed over the past decades to obtain high-affinity ligands for lectin receptors. While multivalency frequently increases the affinity of a ligand for its lectin through the so-called "glycoside cluster effect", the binding profiles towards different lectins have been much less investigated. We have designed a series of multivalent galactosylated glycoconjugates and studied their binding properties towards two lectins, from plant and bacterial origins, to determine their potential selectivity. The synthesis was achieved through copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) under microwave activation between propargylated multivalent scaffolds and an azido-functionalised carbohydrate derivative. The interactions of two galactose-binding lectins from Pseudomonas aeruginosa (PA-IL) and Erythrina cristagalli (ECA) with the synthesized glycoclusters were studied by hemagglutination inhibition assays (HIA), surface plasmon resonance (SPR) and isothermal titration microcalorimetry (ITC). The results obtained illustrate the influence of the scaffold's geometry on the affinity towards the lectin and also on the relative potency in comparison with a monovalent galactoside reference probe. 相似文献
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Valadez-Vega C Alvarez-Manilla G Riverón-Negrete L García-Carrancá A Morales-González JA Zuñiga-Pérez C Madrigal-Santillán E Esquivel-Soto J Esquivel-Chirino C Villagómez-Ibarra R Bautista M Morales-González A 《Molecules (Basel, Switzerland)》2011,16(3):2107-2118
Lectins comprise a heterogeneous class of proteins that recognize the carbohydrate moieties of glycoconjugates with high specificity. Numerous studies have shown that lectins are capable of recognizing specific carbohydrate moieties displayed by malignant cells or tissues. The present work was performed to investigate the effects of tepary bean (Phaseolus acutifolius) lectins on proliferation, colony formation, and alteration of DNA synthesis of human malignant cells. Tepary bean lectin showed dose dependent effects on the inhibition of viability as well as on colony formation in two human malignant cells lines (C33-A, Sw480); By contrast, tepary bean lectin only showed significant effects on DNA synthesis on Sw480 cells. Our results provide evidence of the anti- proliferative and cytotoxic effects of the tepary bean lectins on C33-A and Sw480 cells lines. 相似文献
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Jos A. Villegas Nairiti J. Sinha Naozumi Teramoto Christopher D. Von Bargen Darrin J. Pochan Jeffery G. Saven 《Molecules (Basel, Switzerland)》2022,27(4)
Protein complexes perform a diversity of functions in natural biological systems. While computational protein design has enabled the development of symmetric protein complexes with spherical shapes and hollow interiors, the individual subunits often comprise large proteins. Peptides have also been applied to self-assembly, and it is of interest to explore such short sequences as building blocks of large, designed complexes. Coiled-coil peptides are promising subunits as they have a symmetric structure that can undergo further assembly. Here, an α-helical 29-residue peptide that forms a tetrameric coiled coil was computationally designed to assemble into a spherical cage that is approximately 9 nm in diameter and presents an interior cavity. The assembly comprises 48 copies of the designed peptide sequence. The design strategy allowed breaking the side chain conformational symmetry within the peptide dimer that formed the building block (asymmetric unit) of the cage. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) techniques showed that one of the seven designed peptide candidates assembled into individual nanocages of the size and shape. The stability of assembled nanocages was found to be sensitive to the assembly pathway and final solution conditions (pH and ionic strength). The nanocages templated the growth of size-specific Au nanoparticles. The computational design serves to illustrate the possibility of designing target assemblies with pre-determined specific dimensions using short, modular coiled-coil forming peptide sequences. 相似文献
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Rocha BA Moreno FB Delatorre P Souza EP Marinho ES Benevides RG Rustiguel JK Souza LA Nagano CS Debray H Sampaio AH de Azevedo WF Cavada BS 《Applied biochemistry and biotechnology》2009,152(3):383-393
The unique carbohydrate-binding property of lectins makes them invaluable tools in biomedical research. Here, we report the purification, partial primary structure, carbohydrate affinity characterization, crystallization, and preliminary X-ray diffraction analysis of a lactose-specific lectin from Cymbosema roseum seeds (CRLII). Isolation and purification of CRLII was performed by a single step using a Sepharose-4B-lactose affinity chromatography column. The carbohydrate affinity characterization was carried using assays for hemagglutination activity and inhibition. CRLII showed hemagglutinating activity toward rabbit erythrocytes. O-glycoproteins from mucine mucopolysaccharides showed the most potent inhibition capacity at a minimum concentration of 1.2 microg mL(-1). Protein sequencing by mass spectrometry was obtained by the digestion of CRLII with trypsin, Glu-C, and AspN. CRLII partial protein sequence exhibits 46% similarity with the ConA-like alpha chain precursor. Suitable protein crystals were obtained with the hanging-drop vapor-diffusion method with 8% ethylene glycol, 0.1 M Tris-HCl pH 8.5, and 11% PEG 8,000. The monoclinic crystals belong to space group P2(1) with unit cell parameters a = 49.4, b = 89.6, and c = 100.8 A. 相似文献
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Ying L Liu R Zhang J Lam K Lebrilla CB Gervay-Hague J 《Journal of combinatorial chemistry》2005,7(3):372-384
A glycopeptide library containing more than 500,000 compounds has been constructed from a combination of Asn-linked carbohydrates using one-bead-one-compound combinatorial methodologies. The library was encoded with peptide markers that were topologically segregated on the interior of the solid support to negate interference with carbohydrate/protein recognition during lectin screening. Both the peptide backbone and carbohydrate components were randomized, but the glycosamine was limited to position 3 at the center of the pentapeptide to evaluate the influence of the peptide backbone in lectin recognition. Of the four lectins that were evaluated, remarkable selectivity was observed with wheat germ agglutinin (WGA), which recognizes N-acetyl glucosamine (GlcNAc). From more than 80,000 possible combinations, only six ligands were identified, all possessing GlcNAc. These compounds were independently synthesized, characterized, and evaluated in solution. All six of the glycopeptides showed higher affinity for WGA than GlcNAc, with one having a 4-fold increase. Modeling studies indicate that the peptide backbone is capable of interacting with amino acids in the active site of WGA, but these interactions are not strongly correlated with activity, suggesting that the primary role of the peptide is to properly orient the sugar in the recognition process. 相似文献
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Extracellular superoxide dismutase, EC-SOD, the main superoxide dismutase in biological fluids, is known from its lectin binding to be a glycoprotein. We have characterized the glycosylation of recombinant EC-SOD. A tryptic digest of the protein contained only one glycosylated peptide. This peptide was specifically bound to lectins and stained by periodic acid-Schiff stain. Although appearing very large on size-exclusion chromatography, it was shown to be glycosylated at only one site, asparagine-89, by specific cleavage with glycanases followed by mass spectrometry of the resulting peptide. Based on the binding properties of the peptide to concanavalin A and lentil lectin and the elution profile of N-glycanase-treated glycopeptide on ion-exchange chromatography, the carbohydrate appears to be the complex biantennary type with a core fucose. 相似文献
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Cecioni S Praly JP Matthews SE Wimmerová M Imberty A Vidal S 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(20):6250-6263
The design of multivalent glycoclusters requires the conjugation of biologically relevant carbohydrate epitopes functionalized with linker arms to multivalent core scaffolds. The multigram-scale syntheses of three structurally modified triethyleneglycol analogues that incorporate amide moiety(ies) and/or a phenyl ring offer convenient access to a series of carbohydrate probes with different water solubilities and rigidities. Evaluation of flexibility and determination of preferred conformations were performed by conformational analysis. Conjugation of the azido-functionalized carbohydrates with tetra-propargylated core scaffolds afforded a library of 18 tetravalent glycoclusters, in high yields, by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The compounds were evaluated for their ability to bind to PA-IL (the LecA lectin from the opportunistic pathogen Pseudomonas aeruginosa). Biochemical evaluation through inhibition of hemagglutination assays (HIA), enzyme-linked lectin assays (ELLA), surface plasmon resonance (SPR), and isothermal titration microcalorimetry (ITC) revealed improved and unprecedented affinities for one of the monovalent probes (K(d)=5.8?μM) and also for a number of the tetravalent compounds that provide several new nanomolar ligands for this tetrameric lectin. 相似文献